KR20040047920A - Solid pharmaceutical formulation for a piperazine urea derivative - Google Patents

Abstract

The present invention contains (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof It relates to a solid pharmaceutical formulation.

Description

Solid pharmaceutical preparations for piperazine urea derivatives {SOLID PHARMACEUTICAL FORMULATION FOR A PIPERAZINE UREA DERIVATIVE}

The present invention contains (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof It relates to a solid pharmaceutical formulation.

1 illustrates the solubility of piperazine urea-hydrogen sulfate based on pH.

FIG. 2 shows piperazine urea-hydrogen sulfate in phosphate buffer solution pH 6.8 (33% piperazine urea-hydrogen sulfate and 25% collidone SR®, relative to total weight of tablet) Show the effect of addition of sodium dodecyl sulphate (SDS) on the release.

FIG. 3 shows piperazine urea-hydrogen sulfate in phosphate buffer solution pH 6.8 (33% piperazine urea-hydrogen sulfate and 25% collidone SR®, relative to total weight of tablet) The effect of fumaric acid (%, relative to the total weight of the tablet) on the release is shown.

Figure 4 shows piperazine urea-hydrogen sulfate in phosphate buffer solution pH 6.8 (33% piperazine urea-hydrogen sulfate and 25% collidone SR®, relative to the total weight of the tablet). The effect of the addition of different concentrations of fumaric acid (%, relative to the total weight of the tablet) on the release is shown.

5 shows the release of piperazine urea-hydrogen sulfate (33% piperazine urea-hydrogen sulfate, 25% collidone SR® and 16% fumaric acid, relative to the total weight of the tablet). Show pH effect.

FIG. 6 shows the release of piperazine urea-hydrogen sulfate (33% piperazine urea-hydrogen sulfate, 12.5% collidone SR® and 16% fumaric acid, relative to the total weight of the tablet). Show pH effect.

FIG. 7 shows phases for piperazine urea-hydrogen sulfate (33% piperazine urea-hydrogen sulfate, 25% collidone SR®, 16% fumaric acid and 10% microcrystalline cellulose, tablets; PH effect on the release).

8 shows the particle size distribution of a typical powder forming compound for direct tableting, measured by laser diffractometer.

9 shows the effect of addition of another polymer matrix (Examples 3-9) on the release of piperazine urea-hydrogen sulfate in phosphate buffer solution pH 6.8.

10 shows the effect of addition of other organic acids (Examples 10-13) on the release of piperazine urea-hydrogen sulfate in phosphate buffer solution pH 6.8.

FIG. 11 shows that 100 mg of piperazine urea-hydrogen sulfate was administered in the form of a conventional oral formulation, as well as the formulations mentioned in Examples 1 (Matrix Tablet C) and 2 (Matrix Tablet E). Later, the effect of the pharmaceutical formulation on plasma levels in humans is shown by semilogarithmic visualization.

WO 98/56771 discloses benzylpiperazine urea compounds and in particular (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl Piperazine and its salts are explained. These substances are antagonists of the CCR-1 receptor and are used for the treatment of inflammatory diseases such as multiple sclerosis and rheumatoid arthritis. They are also used for psoriasis and atopic dermatitis. They dissolve very low at basic pH values. At pH 1, from (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine hydrogen sulfate About 5 mg / ml is dissolved, whereas at pH 6.35 or 6.8, in each case only about 0.15 mg / ml or 0.1 mg / ml is dissolved. Because of this very low solubility in the intestine, conventional oral formulations do not reach the therapeutically necessary constant plasma levels while avoiding significant side effects. Moreover, in addition to the increase in solubility in the intestinal tract, the release of the active ingredient is preferably carried out in a controlled manner over an extended period of time such that the dose interval can be significantly increased. At the same time, however, industrial scale manufacture of medicaments had to be possible as well.

In the literature, various methods of increasing the absorption of low soluble active ingredients have been described (eg, "Techniques of Solubilization of Drugs," SH Yalkowsky Ed. In Drugs and the Pharmaceutical). Sciences). For example, the use of (WO01 / 05376) solubilizers, such as surfactants for very low solubility materials, is particularly recommended. However, this method was only insufficiently adequate to solve this problem. (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine hydrogen sulfate of surfactant SDS The addition of causes only a slight increase in release (see FIG. 2).

Other publications deal with the problem of pH-independent release. Streubel et al. (2000, J Controlled Release 67, 101-110) describe the addition of acids to pharmaceuticals. However, the described pharmaceutical substances dissolve very well (above 100 mg / ml) without the addition of acid at pH 6.35. Strutbel et al. Goal was to offset pH-induced fluctuations. This was achieved by the addition of acid. In the present invention, the problem is not only to offset the pH-induced fluctuations, but also to increase the solubility itself. The nature of the pharmaceutical substance described by Strutbel is based on this active ingredient (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluoro Lobenzyl) piperazine is significantly distinguished from the properties. Moreover, the formulations are only used for individual manufacture, not for large scale manufacture of tablets. Therefore, it is not clear whether this method can be used for the problems underlying the present invention.

The present invention contains (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof , Further comprising one or more auxiliaries for direct control of the release of the polymer matrix, organic acid and pH-independent pharmaceuticals (release modification) and to influence the mechanical strength of the dosage form, the particle size of the powder mixture Solves industrial manufacturability simultaneously with problems of increased solubility and pH-independent release by solid pharmaceutical formulations ranging between 0.1 and 750 μm up to 90%.

(2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine is referred to below as piperazine urea and It has the formula:

Preparation of (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine and its salts is described in WO98 / 56771. It is carried out according to the method described in Example 2.

Salts thereof are, for example, hydrochloride, dihydrogen phosphate, hydrogen sulfate, sulfate, mesylate, ethyl sulfonate, malate, fumarate and tartarate.

According to the invention solid pharmaceutical formulations are single-unit systems such as tablets, and multiparticulate systems. The multiparticulate field can be, for example, granular grains, pills or small tablets. The latter can be filled into hard or soft gelatin capsules and compressed into tablets. In almost all cases, the circular body dissolves into many subunits in the stomach. Then a mini-depot is successfully overflowed into the intestine from above. In this case, the mini-depot can normally pass through the pylorus if the sphincter is closed.

The polymer matrix may be a cellulose derivative [eg, methyl cellulose, hydroxypropyl methyl cellulose, (eg hydroxypropyl methyl cellulose K 4 M, hydroxypropyl methyl cellulose K 15 M), hydroxypropyl cellulose, hydroxy Ethyl cellulose, sodium-carboxy methyl cellulose, ethyl cellulose (eg ethyl cellulose 100), cellulose acetate (eg cellulose acetate CA-398-10 NF), cellulose acetate phthalate, cellulose acetate propionate, cellulose acetate Butyrate (eg, cellulose acetate butyrate 171-15 PG), cellulose butyrate, cellulose nitrate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate]; Acrylic derivatives [eg polyacrylates, crosslinked polyacrylates (eg polymethacrylates, polyethylacrylates, polymethyl acid ethyl acrylates, polymethyl acid methacrylates, methyl polymethylates) Methacrylate, polymethylacrylate trimethylammonium ethyl methacrylate chloride, polyethylacrylate trimethylammonium ethyl methacrylate chloride, dimethylaminoethyl methacrylate methacrylate copolymer, Carbopol® 971 P, Carbopol® 974 P, Carbopol® 71 G)], vinyl polymer (e.g. polyvinyl pyrrolidone, polyvinyl acetate, polyvinyl acetate phthalate), polyethylene glycol, polyan Hydride, polyester polyorthoester, polyurethane, polycarbonate, poly Spagens, polyacetals, polysaccharides (eg xanthan, xanthan gum), sugar esters (eg sucrose stearate, sucrose palmitate, sucrose laurate, sucrose behenate, sucrose oleate, sucrose Sucrose esters with erucate and mixed fatty acids), diethylene glycol-monoethyl ether (e.g. Transcutol® P), diethylene glycol monopalmitostearate (e.g. Hydrine®, ethylene glycol monopalmitostearate (e.g. Montyle®), glycerol behenate and glycerol dibehenate (e.g. Compritol) 888 ATO, Comprytol® HD 5 ATO and Comprytol® E), Glycerol Distearate, Glycerol Dipalmitostearate, and Glycerol Palmitostearate (e.g., Fresh) Precirol® ATO 5 and Freshol® WL 2155), Glycerol-Monooleate 40 (e.g., Peceol®), Glycerol-Monostearate 40-55 (Eg Geoleol®), macrogolglycerol-laurate (eg Gelucire® 44/14 and Labrafil®) M 2130 CS), macrogolglycerol-stearate (e.g. Gelucsir® 50/13), propylene glycol-monopalmitostearate (e.g. Monosteol®) ), Chitosan, galactomannan, pectin, shellac and alginate. Particularly suitable as polymer matrix is a physical mixture consisting of water insoluble polyvinyl acetate and water soluble polyvinyl pyrrolidone. This mixture, which further contains sodium lauryl sulfate and silicon dioxide, is, for example, the trade name Collidone SR (Kollidon SR®) (Collidon SR, Technical Information, ME 397e, BASF, July 2000: 80% polyvinyl acetate, 19% polyvinyl pyrrolidone, 0.8% sodium lauryl sulfate and 0.2% silicon dioxide).

Organic acids include fumaric acid, citric acid, trisodium citrate, sodium hydrogen citrate, ascorbic acid, maleic acid, maleic anhydride, tartaric acid, adipic acid, sodium hydrogen phosphate, succinic acid, glutaric acid, glutaric anhydride, potassium sorbate and sorbate It may be selected from the group consisting of formic acid. Fumaric acid is preferred.

Water-soluble or other water-insoluble auxiliaries, such as lactose, calcium phosphate, mannitol, sorbitol, sucrose, fructose, for direct control of pH-independent pharmaceutical release (release modification) and to affect the mechanical strength of the dosage form. , Glucose, starch or starch derivatives may be used. Mixtures of one or more auxiliaries may also be used. Lactose is preferred. Particularly advantageous is roughly grained lactose.

Cellulose or cellulose derivatives can be used for direct control of pH-independent pharmaceutical release (release modification) and as additional auxiliaries to influence the mechanical strength of the dosage form. Particularly advantageous are microcrystalline celluloses. The latter swells in an aqueous environment and results in enhanced pH-independent release of piperazine urea and salts thereof.

In addition, lubricants may be added to single-unit dosage forms, such as tablets, to reduce friction between particles and to reduce sliding friction between material and matrix walls. As lubricant, materials with layers that can move slightly relative to each other because of the lamellar structure are used. Pharmaceutically available organic materials are, for example, divalent metallic soaps, higher fatty alcohols and polyethylene glycols having higher molecular weights. Particularly advantageous are the magnesium and calcium salts of the more expensive fatty acids.

In the case of single-unit dosage forms, flow-controlling agents can be added to enhance the flowability of the material in tablet form. This results in the material in tablet form filling the matrix of the machine uniformly with sufficient packing density. The addition of flow-controlling agents may be particularly necessary in the case of direct tableting. Materials with a pure flow-controlling action are mainly highly dispersed silicic acids, ie micronized silica gel and pyrolytically produced silicic acid. Starch and talc are materials that can be used as flow-controlling agents as well as decomposition aids or lubricants.

In the case of single-unit dosage forms, it is important for industrial scale production that the material in tablet form has granular properties such as good flowability, high bulk density and limited grain size distribution. The grain size of the material in tablet form depends in this case on the size of the tablet to be produced and generally varies between 0.1-750 μm. Within the material in tablet form, separation (eg, during vibration of the tablet machine) And therefore the grain size distribution is important to be as uniform as possible in order to prevent accumulation in the upper part of the material of the larger particles, since otherwise larger variations in dosage may occur. Defined particle size and particle size distribution can be achieved by fractionation (eg, wet or dry sieving) or by granulation of the starting material. Particle size can be measured with the aid of the method described in Example 5. The particle size should be in the range of 0.1-750 μm up to 90%. A range of 20-400 μm is preferred.

Piperazine urea or salts thereof may be homogeneously dispersed within the matrix or surrounded by the matrix. In the latter case, the active ingredient forms a core surrounded by the matrix shell.

Solid pharmaceutical formulations according to the invention can also be coated with pigments to provide a visual and flavorful feeling. The latter generally consists of a binder (eg hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyethylene glycol), a lubricant (eg talc) and a pigment (eg iron oxide pigment, titanium dioxide) .

Preferred solid pharmaceutical formulations are (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof, Lactose, Collidone SR®, Silicon Dioxide and Magnesium Stearate, 90% of the particles range from 0.1-750 μm. Especially preferred is the use of hydrogen sulfate as a salt. Tablets with this formulation show 60% release of piperazine urea after 6 hours.

Another preferred solid pharmaceutical formulation is (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof , Microcrystalline cellulose, lactose, collidone SR®, silicon dioxide and magnesium stearate, with 90% of the particles in the range of 0.1-750 μm. Especially preferred is the use of hydrogen sulfate as a salt. Tablets with this formulation show 80-90% release of piperazine urea after 4 hours.

Another preferred solid pharmaceutical formulation is (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or Salt, lactose, collidone SR®, silicon dioxide and magnesium stearate, with 90% of the particles in the range of 0.1-750 μm, followed by purification of hydroxypropyl methyl cellulose, talc, titanium dioxide And a pigment consisting of an iron oxide pigment. Tablets with this formulation show 60% release of piperazine urea after 6 hours.

Pharmaceutical formulations according to the invention significantly increase the solubility and release of piperazine urea and salts thereof. (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or salts thereof, lactose, corn starch, In the case of conventional formulations consisting of polyvinyl pyrrolidone, croscarmellose sodium and magnesium stearate, only about 10% is released after 8-10 hours at pH 6.8, while only about 60- The emission increases to 90%. The advantages of the pharmaceutical formulations according to the invention are also shown in clinical studies. (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl of the individual being treated compared to conventional oral formulations Plasma levels of piperazine increase with prolonged administration of the formulations according to the invention (see FIG. 11).

The formulations according to the invention have all the properties necessary for industrial scale preparation, for example good fluidity, high bulk density, good dosage accuracy, high plasticity deformability and hence slight compressibility and high mechanical strength of the tablets produced. Has

Subject of the invention is also (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or salts thereof Is a process for preparing a solid pharmaceutical formulation according to the invention, which is mixed with a polymer matrix, an organic acid, a lubricant and an adjuvant and in the form of a tablet (direct tableting). The direct manufacture of the tablets is carried out on the basis of this case via the mixing of one dose of powder components and the subsequent powder mixing through the filling device of the tablet machine. In the case of direct tableting, the particle size and particle size distribution, polymer matrix, organic acids and auxiliaries of the piperazine urea and salts thereof used have a significant impact on the industrial scale preparation of tablets. Therefore, the latter is classified separately (eg by sieving) before mixing the powder components. Alternatively, the whole powder mixture or individual components of the powder mixture can be sorted together (eg sieving). As mentioned in the Examples, the powder components are weighed and are gravity mixers (e.g., turbula mixers, V-mixers) or forced-circulating mixers (e.g., plow blade mixers). In a rotary mixer-kneader). In particular, the flow-regulator and the lubricant (both together referred to as FST composites) are added just before the tableting machine is filled. In this case, the FST composite is sieved finely over the premixed tableting material and mixed as described above, but the mixing time should not be set too short (homogeneous distribution) or too long (overmixing of the materials).

The present invention also relates to (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof, It relates to a process for the preparation of a solid pharmaceutical formulation according to the invention, wherein the polymer matrix, organic acid and adjuvant are subjected to an operation called granulation prior to mixing and tableting. After granulation and addition of lubricant, it is in tablet form as above. Granulation is in this case stepwise expansion or agglomeration of the primary particles of the powder mixture up to the desired secondary size (creation of granulation) or partitioning of the powder material made into a paste into the desired granular grain size (of granulation). Decomposition). Generation of granulations includes, for example, circular granulation and fluidized bed granulation. The decomposition of the granulation can be carried out, for example, by compression of the starting material and subsequent mechanical splitting and sieving of the compressed material. In this case, the decomposition or production of the granulation can be carried out wet (eg, granules of adhesive or hard surface) or dry (eg briquettes or melt-solidified granules).

Another subject of the invention is (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or Salts, polymer matrices, organic acids and auxiliaries (preferably cellulose, cellulose derivatives and lactose) are processed into solid multiparticulate pharmaceutical formulations according to the invention, which are processed into pills by extrusion and subsequent spheronization.

Another subject of the invention is (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or Salts, organic acids and auxiliaries (preferably cellulose, cellulose derivatives and lactose) are processed into solid multiparticulate pharmaceutical preparations according to the invention in which they are processed into pills by extrusion and subsequent spheronization. Pills containing the active ingredient are then coated with a polymer matrix (preferably cellulose derivative, acrylic derivative, vinyl polymer and shellac). In certain circumstances, the active ingredient containing pills may be coated with a subcoat (preferably cellulose derivative and vinyl polymer) before the polymer matrix is applied. The function of the subcoat is (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or salts thereof (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine during incompatibility between the polymer matrix or pill storage Or inhibition of premature diffusion of the salts in the polymer matrix.

Another subject of the invention is (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or Salts and adjuvants (preferably cellulose, cellulose derivatives and lactose) are processed into solid multiparticulate pharmaceutical formulations according to the invention, which are processed into pills by extrusion and subsequent spheronization. Pills containing the active ingredient are then coated with an organic acid and a polymer matrix (preferably cellulose derivatives, acrylic derivatives, vinyl polymers and shellac). In certain circumstances, the active ingredient containing pills may be coated with a subcoat (preferably cellulose derivative and vinyl polymer) before the polymer matrix is applied.

Another subject of the invention is (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or Salts, polymer matrices, organic acids and adjuvants are processes for the preparation of solid multiparticulate pharmaceutical formulations according to the invention in which they are processed into pills by direct pilling. In this case, the starting materials are mixed and processed into pills by binder solution (wet granulation) or melted additives (eg fat).

Another subject of the invention is (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or Salts, polymer matrices, organic acids and auxiliaries are processes for the preparation of solid multiparticulate pharmaceutical preparations according to the invention, wherein the solids are processed into pills by spray-drying or spray-solidifying.

Another subject of the invention is (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or Salts, polymer matrices, organic acids and adjuvants are processes for the preparation of solid multiparticulate pharmaceutical formulations according to the invention in which they are processed into pills by rotor granulation.

The invention also provides a polymeric matrix, an organic acid and an adjuvant for (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl A method for producing a solid pharmaceutical formulation according to the present invention, which is applied layered onto piperazine or a salt thereof and processed into a pill (layer formation).

The invention also relates to (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or salts thereof, polymers A process for the preparation of a solid pharmaceutical formulation according to the invention, wherein the matrix, organic acid and auxiliaries are applied layered onto a core free of active ingredients (so-called non-pareil) and processed into pills. In this method, (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof is generally used. Is first applied onto a core (so-called non-rail) without active ingredient. Next, an organic acid is applied. At the end of the method, the pills are coated with a polymer matrix (preferably cellulose derivatives, acrylic derivatives, vinyl polymers and shellac). In certain circumstances, the pills may be coated with a subcoat (preferably cellulose derivative and vinyl polymer) before the polymer matrix is applied.

The invention also relates to a method of filling a pill prepared in a pharmaceutically used capsule (preferably gelatin capsule, starch capsule or cellulose derivative capsule) or compressing the pill prepared into tablets. The filling of pills into capsules or processing of pills into tablets may optionally be carried out with the addition of other auxiliaries (preferably cellulose, cellulose derivatives, lactose, lubricants and flow-controlling agents).

Subject of the invention is also (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or salts thereof It is a process for the preparation of a solid pharmaceutical preparation according to the invention, which is mixed with a polymer matrix, an organic acid, a lubricant and an adjuvant and then processed by direct tableting into a small tablet (preferably tablet diameter 1-5 mm).

The present invention also relates to (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof, It relates to a process for the preparation of a solid pharmaceutical formulation according to the invention, wherein the polymer matrix, the organic acid and the adjuvant are subjected to an operation called granulation prior to mixing and tableting. After granulation and addition of lubricant, the starting material is processed into small tablets (preferably tablet diameter 1-5 mm).

The invention also relates to a method for filling small tablets made into capsules (preferably gelatin capsules, starch capsules or cellulose derivative capsules) used for pharmaceutical purposes. Filling small tablets into capsules can optionally be performed with the addition of other adjuvants (preferably cellulose, cellulose derivatives, lactose).

The subject of the invention also relates to the use of a solid pharmaceutical preparation according to the invention for the manufacture of a medicament for the treatment of an inflammatory disease. Inflammatory diseases can be, for example, multiple sclerosis, rheumatoid arthritis, psoriasis or atopic dermatitis. Treatment of patients suffering from inflammatory diseases is preferably carried out with one dose during the day.

Example 1 Preparation of Matrix Tablets by Direct Tableting

Composition Per Base Unit:

100 mg piperazine urea-hydrogen sulfate

69 mg lactose

75 mg collidone SR®

50 mg fumaric acid

3 mg of highly dispersed silicon dioxide

3 mg magnesium stearate

Lactose, piperazine urea-hydrogen sulfate and Collidone SR® were each sieved and mixed in Turbula for 10 minutes in this order. Sieved fumaric acid was added and all ingredients were mixed again in the Tourbula for 5 minutes. Sifted highly dispersed silicon dioxide was added and all ingredients were mixed again in the Turbula for 5 minutes. Sifted magnesium stearate was sparged and all the ingredients were mixed again in the Turbula for 30 seconds. The tableting of the powder molding compound was then carried out by an eccentric tablet press or a rotary tablet press.

Example 2 Preparation of Matrix Tablets by Direct Tableting

Composition Per Base Unit:

100 mg piperazine urea-hydrogen sulfate

39 mg lactose

75 mg collidone SR®

50 mg fumaric acid

30 mg microcrystalline cellulose

3 mg of highly dispersed silicon dioxide

3 mg magnesium stearate

Lactose, piperazine urea-hydrogen sulfate, collidone SR® and microcrystalline cellulose were each sieved and mixed in Turbula for 10 minutes in this order. Sieved fumaric acid was added and all ingredients were mixed again in the Tourbula for 5 minutes. Sifted highly dispersed silicon dioxide was added and all ingredients were mixed again in the Turbula for 5 minutes. Sifted magnesium stearate was sparged and all the ingredients were mixed again in the Turbula for 30 seconds. The tableting of the powder molding compound was then carried out by an eccentric tablet press or a rotary tablet press.

Example 3 Preparation of Matrix Tablets by Direct Tableting

Composition Per Base Unit:

100 mg piperazine urea-hydrogen sulfate

104 mg lactose

40 mg of Freshroll® ATO 5

50 mg fumaric acid

3 mg of highly dispersed silicon dioxide

3 mg magnesium stearate

Lactose, piperazine urea-hydrogen sulfate and freshroll® ATO 5 (glycerol dipalmitostearate) were each sieved and mixed in Turbula for 10 minutes in this order. Sieved fumaric acid was added and all ingredients were mixed again in the Tourbula for 5 minutes. Sifted highly dispersed silicon dioxide was added and all ingredients were mixed again in the Turbula for 5 minutes. Sifted magnesium stearate was sparged and all the ingredients were mixed again in the Turbula for 30 seconds. The tableting of the powder molding compound was then carried out by an eccentric tablet press or a rotary tablet press.

Example 4 Preparation of Matrix Tablets by Direct Tableting

Composition Per Base Unit:

100 mg piperazine urea-hydrogen sulfate

104 mg lactose

40 mg of Comprytol® 888 ATO

50 mg fumaric acid

3 mg of highly dispersed silicon dioxide

3 mg magnesium stearate

Lactose, piperazine urea-hydrogen sulphate and Comprytol® 888 ATO (glycerol dibehenate) were each sieved and mixed in Turbula for 10 minutes in this order. Sieved fumaric acid was added and all ingredients were mixed again in the Tourbula for 5 minutes. Sifted highly dispersed silicon dioxide was added and all ingredients were mixed again in the Turbula for 5 minutes. Sifted magnesium stearate was sparged and all the ingredients were mixed again in the Turbula for 30 seconds. The tableting of the powder molding compound was then carried out by an eccentric tablet press or a rotary tablet press.

Example 5 Preparation of Matrix Tablets by Direct Tableting

Composition Per Base Unit:

100 mg piperazine urea-hydrogen sulfate

69 mg lactose

75 mg Carbopol® 71 G

50 mg fumaric acid

3 mg of highly dispersed silicon dioxide

3 mg magnesium stearate

Lactose, piperazine urea-hydrogen sulfate and Carbopol® 71 G (crosslinked polyacrylate) were each sieved and mixed in Turbula for 10 minutes in this order. Sieved fumaric acid was added and all ingredients were mixed again in the Tourbula for 5 minutes. Sifted highly dispersed silicon dioxide was added and all ingredients were mixed again in the Turbula for 5 minutes. Sifted magnesium stearate was sparged and all the ingredients were mixed again in the Turbula for 30 seconds. Purification of the powder molding compound was then carried out by an eccentric tablet press or a rotary tablet press.

Example 6 Preparation of Matrix Tablets by Direct Tableting

Composition Per Base Unit:

100 mg piperazine urea-hydrogen sulfate

69 mg lactose

75 mg of Xanthural® 75

50 mg fumaric acid

3 mg of highly dispersed silicon dioxide

3 mg magnesium stearate

Lactose, piperazine urea-hydrogen sulfate and xantural® 75 (xanthan gum) were each sieved and mixed in Turbula for 10 minutes in this order. Sieved fumaric acid was added and all ingredients were mixed again in the Tourbula for 5 minutes. Sifted highly dispersed silicon dioxide was added and all ingredients were mixed again in the Turbula for 5 minutes. Sifted magnesium stearate was sparged and all the ingredients were mixed again in the Turbula for 30 seconds. The tableting of the powder molding compound was then carried out by an eccentric tablet press or a rotary tablet press.

Example 7 Preparation of Matrix Tablets by Direct Tableting

Composition Per Base Unit:

100 mg piperazine urea-hydrogen sulfate

84 mg lactose

60 mg ethylcellulose 100

50 mg fumaric acid

3 mg of highly dispersed silicon dioxide

3 mg magnesium stearate

Lactose, piperazine urea-hydrogen sulfate and ethylcellulose 100 were each sieved and mixed in Turbula for 10 minutes in this order. Sieved fumaric acid was added and all ingredients were mixed again in the Tourbula for 5 minutes. Sifted highly dispersed silicon dioxide was added and all ingredients were mixed again in the Turbula for 5 minutes. Sifted magnesium stearate was sparged and all the ingredients were mixed again in the Turbula for 30 seconds. The tableting of the powder molding compound was then carried out by an eccentric tablet press or a rotary tablet press.

Example 8 Preparation of Matrix Tablets by Direct Tableting

Composition Per Base Unit:

100 mg piperazine urea-hydrogen sulfate

10 mg lactose

134 mg cellulose acetate butyrate 171-15 pg

50 mg fumaric acid

3 mg of highly dispersed silicon dioxide

3 mg magnesium stearate

Lactose, piperazine urea-hydrogen sulfate and cellulose acetate butyrate 171-15 PG (cellulose acetate butyrate) were each sieved and mixed in Turbula for 10 minutes in this order. Sieved fumaric acid was added and all ingredients were mixed again in the Tourbula for 5 minutes. Sifted highly dispersed silicon dioxide was added and all ingredients were mixed again in the Turbula for 5 minutes. Sifted magnesium stearate was sparged and all the ingredients were mixed again in the Turbula for 30 seconds. The tableting of the powder molding compound was then carried out by an eccentric tablet press or a rotary tablet press.

Example 9 Preparation of Matrix Tablets by Direct Tableting

Composition Per Base Unit:

100 mg piperazine urea-hydrogen sulfate

94 mg lactose

50 mg hydroxypropyl methyl cellulose K 15 M

50 mg fumaric acid

3 mg of highly dispersed silicon dioxide

3 mg magnesium stearate

Lactose, piperazine urea-hydrogen sulfate and hydroxypropyl methyl cellulose K 15 M were each sieved and mixed in Turbula for 10 minutes in this order. Sieved fumaric acid was added and all ingredients were mixed again in the Tourbula for 5 minutes. Sifted highly dispersed silicon dioxide was added and all ingredients were mixed again in the Turbula for 5 minutes. Sieved magnesium stearate was sparged and all the ingredients were mixed again in Turbula for 30 seconds. The tableting of the powder molding compound was then carried out by an eccentric tablet press or a rotary tablet press.

Example 10 Preparation of Matrix Tablets by Direct Tableting

Composition Per Base Unit:

100 mg piperazine urea-hydrogen sulfate

69 mg lactose

75 mg collidone SR®

50 mg glutaric acid

3 mg of highly dispersed silicon dioxide

3 mg magnesium stearate

Lactose, piperazine urea-hydrogen sulfate and Collidone SR® were each sieved and mixed in Turbula for 10 minutes in this order. Sifted glutaric acid was added and all ingredients were mixed again in the Tourbula for 5 minutes. Sifted highly dispersed silicon dioxide was added and all ingredients were mixed again in the Turbula for 5 minutes. Sifted magnesium stearate was sparged and all the ingredients were mixed again in the Turbula for 30 seconds. The tableting of the powder molding compound was then carried out by an eccentric tablet press or a rotary tablet press.

Example 11 Preparation of Matrix Tablets by Direct Tableting

Composition Per Base Unit:

100 mg piperazine urea-hydrogen sulfate

69 mg lactose

75 mg collidone SR®

50 mg tartaric acid

3 mg of highly dispersed silicon dioxide

3 mg magnesium stearate

Lactose, piperazine urea-hydrogen sulfate and Collidone SR® were each sieved and mixed in Turbula for 10 minutes in this order. Sifted tartaric acid was added and all the ingredients were mixed again in Turbula for 5 minutes. Sifted highly dispersed silicon dioxide was added and all ingredients were mixed again in the Turbula for 5 minutes. Sifted magnesium stearate was sparged and all the ingredients were mixed again in the Turbula for 30 seconds. The tableting of the powder molding compound was then carried out by an eccentric tablet press or a rotary tablet press.

Example 12 Preparation of Matrix Tablets by Direct Tableting

Composition Per Base Unit:

100 mg piperazine urea-hydrogen sulfate

69 mg lactose

75 mg collidone SR®

50 mg adipic acid

3 mg of highly dispersed silicon dioxide

3 mg magnesium stearate

Lactose, piperazine urea-hydrogen sulfate and Collidone SR® were each sieved and mixed in Turbula for 10 minutes in this order. Sieved adipic acid was added and all the ingredients were mixed again in Turbula for 5 minutes. Sifted highly dispersed silicon dioxide was added and all ingredients were mixed again in the Turbula for 5 minutes. Sifted magnesium stearate was sparged and all the ingredients were mixed again in the Turbula for 30 seconds. The tableting of the powder molding compound was then carried out by an eccentric tablet press or a rotary tablet press.

Example 13 Preparation of Matrix Tablets by Direct Tableting

Composition Per Base Unit:

100 mg piperazine urea-hydrogen sulfate

69 mg lactose

75 mg collidone SR®

50 mg of ascorbic acid

3 mg of highly dispersed silicon dioxide

3 mg magnesium stearate

Lactose, piperazine urea-hydrogen sulfate and Collidone SR® were each sieved and mixed in Turbula for 10 minutes in this order. Sieved ascorbic acid was added and all ingredients were mixed again in the Tourbula for 5 minutes. Sifted highly dispersed silicon dioxide was added and all ingredients were mixed again in the Turbula for 5 minutes. Sifted magnesium stearate was sparged and all the ingredients were mixed again in the Turbula for 30 seconds. The tableting of the powder molding compound was then carried out by an eccentric tablet press or a rotary tablet press.

Example 14 Preparation of Matrix Tablets by Subsequent Membrane Coating with Direct Tableting

Composition Per Base Unit:

100 mg piperazine urea-hydrogen sulfate

82.5 mg lactose

60 mg collidone SR®

50 mg fumaric acid

3 mg of highly dispersed silicon dioxide

4.5 mg magnesium stearate

7.6 mg hydroxypropyl methyl cellulose, viscosity 5

1.5 mg talc

5.9 mg titanium dioxide, E 171

0.02 mg of iron oxide pigment yellow, E 172 (EOP yellow)

Lactose, piperazine urea-hydrogen sulfate and Collidone SR® were each sieved and mixed in Turbula for 10 minutes in this order. Sieved fumaric acid was added and all ingredients were mixed again in the Tourbula for 5 minutes. Sifted highly dispersed silicon dioxide was added and all ingredients were mixed again in the Turbula for 5 minutes. Sifted magnesium stearate was sparged and all the ingredients were mixed again in the Turbula for 30 seconds. The tableting of the powder molding compound was then carried out by an eccentric tablet press or a rotary tablet press (tablet core). Talc, iron oxide pigment yellow and titanium dioxide are suspended in water (eg Ultra-Turrax mixer or colloid mill) in water (dye suspension). Hydroxypropyl methyl cellulose was dissolved in water (e.g., ultra-turax mixer or colloid mill) in water (binder solution). The dye suspension and binder solution were combined (eg, ultra-turax mixer or colloid mill) with stirring (membrane coating). The membrane coating prepared was sprayed onto the tablet cores in a drum coater while supplying heat and the water used was evaporated.

Example 15 Preparation of Matrix Tablets by Subsequent Membrane Coating with Direct Tableting

Composition Per Base Unit:

300 mg of piperazine urea-hydrogen sulfate

247.5 mg lactose

180 mg collidone SR®

150 mg fumaric acid

9 mg of highly dispersed silicon dioxide

13.5 mg magnesium stearate

10.1 mg hydroxypropyl methyl cellulose, viscosity 5

2 mg talc

7.8 mg titanium dioxide, E 171

0.03 mg of iron oxide pigment yellow, E 172 (EOP yellow)

Lactose, piperazine urea-hydrogen sulfate and Collidone SR® were each sieved and mixed in Turbula for 10 minutes in this order. Sieved fumaric acid was added and all ingredients were mixed again in the Tourbula for 5 minutes. Sifted highly dispersed silicon dioxide was added and all ingredients were mixed again in the Turbula for 5 minutes. Sifted magnesium stearate was sparged and all the ingredients were mixed again in the Turbula for 30 seconds. The tableting of the powder molding compound was then carried out by an eccentric tablet press or a rotary tablet press (tablet core). Talc, iron oxide pigment yellow and titanium dioxide were suspended in water (eg, ultra-turax mixer or colloid mill) in water (dye suspension). Hydroxypropyl methyl cellulose was dissolved in water (e.g., ultra-turax mixer or colloid mill) in water (binder solution). The dye suspension and binder solution were combined (eg, ultra-turax mixer or colloid mill) with stirring (membrane coating). The membrane coating prepared was sprayed onto the tablet cores in a drum coater while supplying heat and the water used was evaporated.

Example 16 Preparation of Small Tablets by Direct Tableting

10 mg of piperazine urea-hydrogen sulfate

6.9 mg lactose

7.5 mg collidone SR®

5 mg fumaric acid

0.3 mg of highly dispersed silicon dioxide

0.3 mg magnesium stearate

Lactose, piperazine urea-hydrogen sulfate and Collidone SR® were each sieved and mixed in Turbula for 10 minutes in this order. Sieved fumaric acid was added and all ingredients were mixed again in the Tourbula for 5 minutes. Sifted highly dispersed silicon dioxide was added and all ingredients were mixed again in the Turbula for 5 minutes. Sifted magnesium stearate was sparged and all the ingredients were mixed again in the Turbula for 30 seconds. The tableting of the powdered compound into small tablets was then carried out by an eccentric tablet press or a rotary tablet press. The prepared small tablets were delivered into hard gelatin capsules.

Example 17 Preparation of Subsequent Membrane Coated Small Tablets

Composition Per Base Unit:

10 mg of piperazine urea-hydrogen sulfate

8.25 mg lactose

6 mg collidone SR®

5 mg fumaric acid

0.3 mg of highly dispersed silicon dioxide

0.45 mg magnesium stearate

0.76 mg hydroxypropyl methyl cellulose, viscosity 5

0.15 mg talc

0.59 mg titanium dioxide, E 171

0.002 mg iron oxide pigment yellow, E 172 (EOP yellow)

Lactose, piperazine urea-hydrogen sulfate and Collidone SR® were each sieved and mixed in Turbula for 10 minutes in this order. Sieved fumaric acid was added and all ingredients were mixed again in the Tourbula for 5 minutes. Sifted highly dispersed silicon dioxide was added and all ingredients were mixed again in the Turbula for 5 minutes. Sifted magnesium stearate was sparged and all the ingredients were mixed again in the Turbula for 30 seconds. The tableting of the powdered compound into small tablets was then carried out by an eccentric tablet press or a rotary tablet press (tablet core). Talc, iron oxide pigment yellow and titanium dioxide were suspended in water (eg, ultra-turax mixer or colloid mill) in water (dye suspension). Hydroxypropyl methyl cellulose was dissolved in water (e.g., ultra-turax mixer or colloid mill) in water (binder solution). The dye suspension and binder solution were combined (eg, ultra-turax mixer or colloid mill) with stirring (membrane coating). The membrane coating prepared was sprayed onto the tablet cores in a drum coater while supplying heat and the water used was evaporated. The prepared small tablets were delivered into hard gelatin capsules.

Example 18 Preparation of Matrix Tablets After Granulation

Composition Per Base Unit:

100 mg piperazine urea-hydrogen sulfate

72 mg lactose

75 mg collidone SR®

50 mg fumaric acid

3 mg magnesium stearate

Lactose, piperazine urea-hydrogen sulfate, collidone SR® and fumaric acid were placed in a fluid bed granulator and granulated with water spray. Magnesium stearate was sprayed onto the dried granules and mixed in the Tourbula for 30 seconds. The tableting of the granules was then carried out by an eccentric tablet press or a rotary tablet press.

Example 19 Preparation of Small Tablets After Granulation

Composition Per Base Unit:

10 mg of piperazine urea-hydrogen sulfate

7.2 mg lactose

7.5 mg collidone SR®

5 mg fumaric acid

0.3 mg magnesium stearate

Lactose, piperazine urea-hydrogen sulfate, collidone SR® and fumaric acid were placed in a fluid bed granulator and granulated with water spray. Magnesium stearate was sprayed onto the dried granules and mixed in the Tourbula for 30 seconds. The tableting of the granules into small tablets was then carried out by an eccentric tablet press or a rotary tablet press. The prepared small tablets were delivered into hard gelatin capsules.

Example 20 Preparation of Pills by Extrusion and Spherization

Composition per capsule:

60 mg of piperazine urea-hydrogen sulfate

30 mg microcrystalline cellulose

10 mg fumaric acid

25.5 mg Eudragit® NE 30 D

4.25 mg talc

0.18 mg of highly-dispersed anhydrous silicon dioxide

Piperazine urea-hydrogen sulphate, microcrystalline cellulose and fumaric acid were processed into pills by the Nica-pelletizing system. In this method, piperazine urea-hydrogen sulfate, microcrystalline cellulose and fumaric acid were first mixed in the dry state. The powder mixture was then extruded with the addition of water. Processing of the extrudate into pills was carried out using a spheronizer. An aqueous suspension consisting of Eudragit® NE 30 D and talc was sprayed onto the pills using Urster while supplying heat by fluid bed granulator. Delivery of the membrane coated pills into hard gelatin capsules was performed with the addition of silicon dioxide.

Example 21 Measurement of Release of Piperazine Urea-Hydrogen Sulfate

Active ingredient release measurements are described in U.S. Pat. Pharmacopeia USP XXIV], according to the one-compartment method (vane-stirrer apparatus). The release of piperazine urea-hydrogen sulphate was examined at pH 1 (0.1 N hydrochloric acid) and phosphate buffer solutions, pH 4.5 and 6.8 (see composition USP XXIV). In order to adjust the immersion conditions which ensure that the release of piperazine urea-hydrogen sulphate is mainly controlled by the formulation, a surfactant (SDS) or hydroxypropyl-β-cyclodextrin is added to the release medium if necessary.

Example 22 Determination of Particle Size

The particle sizes of the piperazine urea-hydrogen sulfates, lactose, collidone SR®, fumaric acid, microcrystalline cellulose or powder mixtures mentioned in Examples 1 to 9 were determined by laser diffractometer (muller, egg). Muer, RH, Schuhmann, R., Teilchengroe β enmessung in der Laborpraxis [Particle Size Measurement in Laboratory Practice], Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1996). As a measurement parameter, the volume distribution of particle size was used.

Claims (24)

(2R) -1-((4), further comprising a polymer matrix, an organic acid, a lubricant and one or more auxiliaries, wherein the particle size of the powder mixture ranges between 0.1 and 750 μm up to 90%. A solid pharmaceutical formulation containing -chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof. The method of claim 1, wherein the polymer matrix is a cellulose derivative, acrylic derivative, vinyl polymer, polyanhydride, polyester polyorthoester, polyurethane, polycarbonate, polyphosphazene, polyacetal, polysaccharide, sugar Esters, diethylene glycol-monoethyl ether, diethylene glycol monopalmitostearate, ethylene glycol-monopalmitostearate, glycerol behenate and glycerol dibehenate, glycerol distearate and glycerol palmitostearate, glycerol- Monooleate 40, glycerol-monostearate 40-55, macrogolglycerol-laurate, macrogolglycerol-stearate, propylene glycol-monopalmitostearate, chitosan, galactomannan, pectin, shellac and alginate Solid pharmaceutical formulations selected from the group consisting of. 3. A solid pharmaceutical formulation according to claim 1 or 2 wherein said polymer matrix consists of a mixture of water soluble polyvinyl pyrrolidone and water insoluble polyvinyl acetate. The solid pharmaceutical formulation of claim 1, wherein the polymer matrix has a composition of 80% polyvinyl acetate, 19% polyvinyl pyrrolidone, 0.8% sodium lauryl sulfate and 0.2% silicon dioxide. The organic acid according to any one of claims 1 to 4, wherein the organic acid is fumaric acid, citric acid, trisodium citrate, sodium hydrogen citrate, ascorbic acid, maleic acid, maleic anhydride, tartaric acid, adipic acid, sodium hydrogen phosphate, succinic acid, A solid pharmaceutical formulation selected from the group consisting of glutaric acid, glutaric anhydride, potassium sorbate and sorbic acid. The solid pharmaceutical formulation according to any one of claims 1 to 5, wherein additional lubricant is added. The solid pharmaceutical formulation according to any one of claims 1 to 6, wherein said adjuvant is lactose, calcium phosphate, mannitol or starch. 8. A solid pharmaceutical formulation according to any one of claims 1 to 7, which contains microcrystalline cellulose as an additional adjuvant. 9. The solid pharmaceutical formulation of claim 1, further comprising a flow-controlling agent. 10. The solid pharmaceutical formulation of claim 1, wherein the particle size of the powder mixture is in the range between 20 and 400 μm up to 90%. The compound according to any one of claims 1 to 10, wherein the (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluoro A solid pharmaceutical formulation in which benzyl) piperazine or a salt thereof is homogeneously dispersed in a matrix. The compound according to any one of claims 1 to 11, wherein the (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluoro Lobenzyl) piperazine or a salt thereof is a solid pharmaceutical formulation surrounded by a matrix. One or more of (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or salts thereof The solid according to any one of claims 1 to 12, mixed with an adjuvant, a polymer matrix, an organic acid and a lubricant, in the form of a tablet, and all materials are present in powder form and classified together individually or after mixing. Method for the preparation of a pharmaceutical formulation. One or more of (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or salts thereof 13. A process for the preparation of the solid pharmaceutical formulation according to any one of claims 1 to 12, which is mixed with an adjuvant, a polymer matrix and an organic acid and then granulated and then added with a lubricant and then in the form of a tablet. (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof, polymer matrix, organic acid And a process for preparing the solid multiparticulate pharmaceutical formulation according to any one of claims 1 to 12, wherein the adjuvant is processed into pills by extrusion and subsequent spheronization. (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof, polymer matrix, organic acid And a process for preparing a solid multiparticulate pharmaceutical formulation according to any one of claims 1 to 12, wherein the adjuvant is mixed and processed into a pill with binder solution or dissolved additive. (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof, polymer matrix, organic acid And a process for preparing the solid multiparticulate pharmaceutical formulation according to any one of claims 1 to 12, wherein the adjuvant is processed into a pill by spray-drying or spray-solidifying. (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof, polymer matrix, organic acid And a process for preparing the solid multiparticulate pharmaceutical formulation according to any one of claims 1 to 12, wherein the adjuvant is processed into pills by rotor granulation. The polymer matrix, organic acid and auxiliaries may be (2R) -1-((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or A method for producing a solid pharmaceutical formulation according to any one of claims 1 to 12, which is applied layerwise onto a salt thereof and processed into a pill. Use of a solid pharmaceutical formulation according to any one of claims 1 to 12 for the manufacture of a medicament for the treatment of inflammatory diseases. The use of claim 20, wherein the inflammatory disease is multiple sclerosis. 21. The use according to claim 20, wherein said inflammatory disease is rheumatoid arthritis. The use of claim 20, wherein said inflammatory disease is psoriasis. The use of claim 20, wherein the inflammatory disease is atopic dermatitis.